Research Project
6210394
Feasibility of a coupled-enzyme process to attach the aminoethyl group to the 3-positions of substituted indoles will be investigated. This process is offered as an alternative to existing synthetic methods, which are often not utilized in drug development for reasons discussed. Tryptophan synthase and aromatic amino acid decarboxylase will be obtained from overexpressing strains of E. coli and from pig kidney, respectively. Substrate requirements for each enzyme will be determined by qualitative screening using TLC, and quantitative enzyme activity measurements. Substituted tryptamine targets will include O-methylserotonin, 5-(hydroxymethyl)tryptamine, and key intermediates in the syntheses of selective melatonin ML1 and ML2 receptor ligands luzindole and 2-I-MCA-NAT. Additional screening of enzyme substrates will include a number of commercially-available substituted indoles and tryptophans, in order to test the substrate ranges of the individual and coupled enzyme systems. Conditions for tryptamine syntheses will be optimized for batch reactions and additional tests of 2-phase aqueous/organic solvent and immobilized enzyme reactor systems, which may improve productivity simplify product isolation, will be conducted. PROPOSED COMMERCIAL APPLICATIONS: The process proposed may provide faster access to key pharmaceutical intermediates. Costs for substituted tryptamine pharmaceutical intermediates could be reduced by an efficient route from substituted indoles. Similarly, short routes to neuroreceptor probes would increase the market for these compounds as research tools by reducing prices.
